# ZIP8-dependent Zinc Metabolic Regulation in Alveolar Progenitor Cell Aging and Fibrosis

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2022 · $544,545

## Abstract

Abstract
With the rapid growth of an aging population worldwide, the annual incidences of aging-associated lung diseases
such as idiopathic pulmonary fibrosis (IPF), are increasing. Therefore, there is a great need to comprehensively
investigate the complex process of lung aging and develop interventions to extend the health span of the elderly
population. Type 2 alveolar epithelial cells (AEC2s) function as progenitor cells that maintain epithelium
homeostasis and repair the lung after injury. A characteristic of the aging lung is progenitor cell exhaustion and,
in turn, impairs alveolar regeneration. Persistent epithelial cell injury coupled with inadequate alveolar epithelial
repair due to progenitor cell failure results in a prototype of age-associated lung disease, IPF. In fact, it has been
argued that IPF is a disease of premature aging of AEC2s. Hence, studies focusing on re-activating and/or
expanding AEC2 progenitor cells in lung aging are needed.
As we reported, AEC2 progenitor cells are exhausted in human IPF lungs. IPF AEC2s fail to regenerate in
organoid assays relative to normal AEC2s. In our preliminary studies for this application, we found a decrease
in AEC2 renewal capacity and a loss of AEC2 population occur during lung aging. We aimed to uncover the
molecular mechanisms that contribute to impaired AEC2 renewal during aging, with the long-term goal of pointing
the way to novel interventions that can rejuvenate aged AEC2s. We have found that: 1) The renewal capacity of
AEC2s in 18-20 months old aged mouse lungs are reduced just as what we observed with IPF lungs; 2) Using
single cell RNA-seq and flow cytometry, we identified a deficiency of a specific zinc transporter SLC39A8
(encoding ZIP8) in AEC2s from 18-20 months old aged mouse lungs and IPF lungs; 3) Sirtuin signaling pathway
was downregulated in AEC2s from bleomycin-injured old mouse lungs and IPF lungs; 4) ZIP8 regulates AEC2
progenitor function through SIRT1 and ZIP8/SIRT1 axis is required for AEC2 renewal. In addition, we have
generated a novel mouse model of Zip8 deficiency in AEC2 cells that reveals phenotypes of premature AEC2
aging. Based on these novel findings, we hypothesize that ZIP8 deficiency occurs in AEC2s with aging and
downregulates SIRT1, thereby impairing AEC2 progenitor cell renewal. Furthermore, we propose that
restoring critical components of the ZIP8/zinc/SIRT1 pathway will improve AEC2 progenitor activity and, thus
maintain lung epithelial integrity and prevent age-associated lung diseases.

## Key facts

- **NIH application ID:** 10504940
- **Project number:** 1R01AG078655-01
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Carol Jiurong Liang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $544,545
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10504940

## Citation

> US National Institutes of Health, RePORTER application 10504940, ZIP8-dependent Zinc Metabolic Regulation in Alveolar Progenitor Cell Aging and Fibrosis (1R01AG078655-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10504940. Licensed CC0.

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